Long-Term Renal Function with Cardiac Contractility Modulation Therapy.

BACKGROUND: Cardiac implantable electrical devices are able to affect kidney function through hemodynamic improvements. The Cardiac Contractility Modulation (CCM) is a device-based therapy option for patients with symptomatic chronic heart failure (HF) despite optimized medical treatment. The long-term cardiorenal interactions for CCM treated patients are yet to be described. METHODS: CCM recipients (n=187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were evaluated in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of kidney function, and the chronic kidney disease (CKD) stage-distribution. With regard to kidney function at baseline, the patients were furthermore grouped to either advanced CKD (aCKD, CKD-stage ≥3, eGFR≤59mL/min/1.73 m2, n=107) or preserved kidney function and mild CKD (pCKD, CKD stages 1-2, eGFR≥60mL/min/1.73 m2, n=80). The groups were compared for differences regarding kidney function, New York Heart Association classification (NYHA), biventricular systolic function, HF hospitalizations and other parameters in the long-term (60 months). RESULTS: CKD stage distribution remained stable during the entire follow-up (p=0.65). An increase in serum creatinine (1.47±1 vs. 1.6±1mg/dL) with a corresponding decline of eGFR (58.2±23.4 vs. 54.2±24.4mL/min/1.73 m2, both p<.05) were seen after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3±1.3 vs. 55.3±1.2months, p=0.53) was comparable in both groups. Improvements in NYHA (3.11±0.46 vs. 2.94±0.41 to 2.28±0.8 vs. 1.94±0.6) and LVEF (24.8±7.1 vs. 22.9±6.6 to 31.1±11.4 vs. 35.5±11.1%) were likewise similar after 60 months (both p <.05). The aCKD patients suffered from more HF-hospitalizations and ventricular tachycardias during the entire follow-up period (both p<.05). CONCLUSIONS: The kidney function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experience improvements in LVEF and functional status, regardless of their kidney function before. An impaired kidney function might be associated with further cardiovascular comorbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterwards.

Long-term outcomes from upgrade to cardiac resynchronisation therapy in ischaemic versus non-ischaemic heart disease.

BACKGROUND: Cardiac resynchronisation therapy (CRT) can be necessary in patients with chronic heart failure, who have already been provided with transvenous cardiac implantable electrical devices. Upgrade procedures revealed controversial results, while long-term outcomes regarding underlying Ischaemic- (ICM) or Non-Ischaemic heart disease (NICM) have yet to be described. METHODS: The Mannheim Cardiac Resynchronisation Therapy Registry (MARACANA) was designed as a retrospective observational single-centre registry, including all CRT implantations from 2013-2021 (n = 459). CRT upgrades (n = 136) were retrospectively grouped to either ICM (n = 84) or NICM (n = 52) and compared for New York Heart Association classification (NYHA), paced QRS-width, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE) and other heart failure modification aspects in the long-term (59.3 ± 5 months). RESULTS: Baseline-characteristics including paced QRS-width, upgrade indications or NYHA-classification were comparable for both groups (group comparison p>.05). The CRT upgrade improved NYHA (ICM: 2.98 ± 0.4 to 2.29 ± 0.7, NICM: 2.94 ± 0.5 to 2.08 ± 0.5) and the LVEF (ICM: 27.2 ± 6.6 to 38.25 ± 8.8, NICM: 30.2 ± 9.4 to 38.7 ± 13.8%) after five years, irrespective of underlying heart disease (each group p < .05, group comparison p>.05). Only ICM revealed significant improvements in TAPSE (15.9 ± 4.1 to 18.9 ± 4.1 mm) and narrowing of the paced QRS-width (185.4 ± 29 to 147.2 ± 16.3 ms) after five years (each p < .05). CONCLUSIONS: Upgrade to CRT might improve heart failure symptoms and left-ventricular systolic function in the long-term, irrespective of underlying ischaemic or non-ischaemic heart disease.

Should HFrEF patients with NYHA class II expect benefit from CCM therapy? Results from the MAINTAINED observational study.

BACKGROUND: Cardiac contractility modulation (CCM) is an FDA-approved device therapy for patients with refractory systolic heart failure and normal QRS width. Randomized trials demonstrated benefits of CCM primarily for patients with severe heart failure (> NYHA class II). PURPOSE: To better understand individualized indication in clinical practice, we compared the effect of CCM in patients with baseline NYHA class II vs. NYHA class III or ambulatory IV over the 5-year period in our large clinical registry (MAINTAINED Observational Study). METHODS: Changes in NYHA class, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), NT-proBNP level, and KDIGO chronic kidney disease stage were compared as functional parameters. In addition, mortality within 3 years was compared with the prediction of the Meta-Analysis Global Group in Chronic heart failure risk score. RESULTS: A total of 172 patients were included in the analyses (10% with NYHA class II). Only patients with NYHA class III/IV showed a significant improvement in NYHA class over 5 years of CCM (II: 0.1 ± 0.6; p = 0.96 vs. III/IV: - 0.6 ± 0.6; p < 0.0001). In both groups, LVEF improved significantly (II: 4.7 ± 8.3; p = 0.0072 vs. III/IV: 7.0 ± 10.7%; p < 0.0001), while TAPSE improved significantly only in NYHA class III/IV patients (II: 2.2 ± 1.6; p = 0.20 vs. III/IV: 1.8 ± 5.2 mm; p = 0.0397). LVEF improvement was comparable in both groups over 5 years of CCM (p = 0.83). NYHA class II patients had significantly lower NT-proBNP levels at baseline (858 [175/6887] vs. 2632 [17/28830] ng/L; p = 0.0044), which was offset under therapy (399 [323/1497] vs. 901 [13/18155] ng/L; p = 0.61). Actual 3-year mortality was 17 and 26% vs. a predicted mortality of 31 and 42%, respectively (p = 0.0038 for NYHA class III/IV patients). CONCLUSIONS: NYHA class III/IV patients experienced more direct and extensive functional improvements with CCM and a survival benefit compared with the predicted risk. However, our data suggest that NYHA class II patients may also benefit from the sustained positive effects of LVEF improvement.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

The development of the extravascular defibrillator with substernal lead placement: A new Frontier for device-based treatment of sudden cardiac arrest.

INTRODUCTION: The extravascular implantable cardioverter-defibrillato (EV ICD) system with substernal lead placement is a novel nontransvenous alternative to current commercially available ICD systems. The EV ICD provides defibrillation and pacing therapies without the potential long-term complications of endovascular lead placement but requires a new procedure for implantation with a safety profile under evaluation. METHODS: This paper summarizes the development of the EV ICD, including the preclinical and clinical evaluations that have contributed to the system and procedural refinements to date. RESULTS: Extensive preclinical research evaluations and four human clinical studies with >140 combined acute and chronic implants have enabled the development and refinement of the EV ICD system, currently in worldwide pivotal study. CONCLUSION: The EV ICD may represent a clinically valuable solution in protecting patients from sudden cardiac death while avoiding the long-term consequences of transvenous hardware. The EV ICD offers advantages over transvenous and subcutaneous systems by avoiding placement in the heart and vasculature; relative to subcutaneous systems, EV ICD requires less energy for defibrillation, enabling a smaller device, and provides pacing features such as antitachycardia and asystole pacing in a single system.

Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial.

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks. METHODS: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population. RESULTS: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05). CONCLUSIONS: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

Cardiac Contractility Modulation in Patients with Ischemic versus Non-ischemic Cardiomyopathy: Results from the MAINTAINED Observational Study.

BACKGROUND: Cardiac contractility modulation (CCM) is an FDA-approved device-based therapy for patients with systolic heart failure and normal QRS width who are symptomatic despite optimal drug therapy. The purpose of this study was to compare the long-term therapeutic effects of CCM therapy in patients with ischemic (ICM) versus non-ischemic cardiomyopathy (NICM). METHODS: Changes in NYHA class, KDIGO CKD stage, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), and NT-proBNP levels were compared as functional parameters. Moreover, observed mortality rates at 1 and 3 years were compared to those predicted by the MAGGIC heart failure risk score, and observed mortality rates were compared between groups for the entire follow-up period. RESULTS: One hundred and seventy-four consecutive patients with chronic heart failure and CCM device implantation between 2002 and 2019 were included in this retrospective analysis. LVEF was significantly higher in NICM patients after 3 years of CCM therapy (35 ± 9 vs. 30 ± 9%; p = 0.0211), and after 5 years, also TAPSE of NICM patients was significantly higher (21 ± 5 vs. 18 ± 5%; p = 0.0437). There were no differences in other effectiveness parameters. Over the entire follow-up period, 35% of all patients died (p = 0.81); only in ICM patients, mortality was lower than predicted at 3 years (35 vs. 43%, p = 0.0395). CONCLUSIONS: Regarding improvement of biventricular systolic function, patients with NICM appear to benefit particularly from CCM therapy.

Rationale and design of the PRAETORIAN-DFT trial: A prospective randomized CompArative trial of SubcutanEous ImplanTable CardiOverter-DefibrillatoR ImplANtation with and without DeFibrillation testing.

In transvenous implantable cardioverter-defibrillator (TV-ICD) implants, routine defibrillation testing (DFT) does not improve shock efficacy or reduce arrhythmic death but patients are exposed to the risk of complications related to DFT. The conversion rate of DFT in subcutaneous ICD (S-ICD) is high and first shock efficacy is similar to TV-ICD efficacy rates. STUDY DESIGN: The PRAETORIAN-DFT trial is an investigator-initiated, randomized, controlled, multicenter, prospective two-arm trial designed to demonstrate non-inferiority of omitting DFT in patients undergoing S-ICD implantation in which the S-ICD system components are optimally positioned. Positioning of the S-ICD will be assessed with the PRAETORIAN score. The PRAETORIAN score is developed to systematically evaluate implant position of the S-ICD system components which determine the defibrillation threshold on post-operative chest X-ray. A total of 965 patients, scheduled to undergo a de novo S-ICD implantation without contra-indications for either DFT strategy, will be randomized to either standard of care S-ICD implantation with DFT, or S-ICD implantation without DFT but with evaluation of the implant position using the PRAETORIAN score. The study is powered to claim non-inferiority of S-ICD implantation without DFT in de novo S-ICD patients in respect to the primary endpoint of first shock efficacy in spontaneous arrhythmia episodes. Patients with a high PRAETORIAN score (≥90) in the interventional arm of this study will undergo DFT according to the same DFT protocol as in the control arm. CONCLUSION: The PRAETORIAN-DFT trial is a randomized trial that aims to gain scientific evidence to safely omit a routine DFT after S-ICD implantation in patients with correct device positioning.

Implant and Midterm Outcomes of the Subcutaneous Implantable Cardioverter-Defibrillator Registry: The EFFORTLESS Study.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to defibrillate ventricular arrhythmias, avoiding drawbacks of transvenous leads. The global EFFORTLESS S-ICD (Evaluation oF FactORs ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD) registry is collecting outcomes in 985 patients during a 5-year follow-up. OBJECTIVES: The primary goal of the EFFORTLESS registry is to determine the safety of the S-ICD by evaluating complications and inappropriate shock rate. METHODS: This is the first report on the full patient cohort and study endpoints with follow-up ≥1 year. The predefined endpoints are 30- and 360-day complications, and shocks for atrial fibrillation or supraventricular tachycardia. RESULTS: Patients were followed for 3.1 ± 1.5 years and 82 completed the study protocol 5-year visit. Average age was 48 years, 28% were women, ejection fraction was 43 ± 18%, and 65% had a primary prevention indication. The S-ICD system and procedure complication rate was 4.1% at 30 days and 8.4% at 360 days. The 1-year complication rate trended toward improvement from the first to last quartile of enrollment (11.3% [quartile 1]) to 7.8% [quartile 2], 6.6% [quartile 3], and 7.4% [quartile 4]; quartile 1 vs. quartiles 2 to 4; p = 0.06). Few device extractions occurred due to need for antitachycardia (n = 5), or biventricular (n = 4) or bradycardia pacing (n = 1). Inappropriate shocks occurred in 8.1% at 1 year and 11.7% after 3.1 years. At implant, 99.5% of patients had a successful conversion of induced ventricular tachycardia or ventricular fibrillation. The 1- and 5-year rates of appropriate shock were 5.8% and 13.5%, respectively. Conversion success for discrete spontaneous episodes was 97.4% overall. CONCLUSIONS: This registry demonstrates that the S-ICD fulfills predefined endpoints for safety and efficacy. Midterm performance rates on complications, inappropriate shocks, and conversion efficacy were comparable to rates observed in transvenous implantable cardioverter-defibrillator studies. (Evaluation oF Factors ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD [The EFFORTLESS S-ICD Registry]; NCT01085435).

Incremental benefit of late gadolinium cardiac magnetic resonance imaging for risk stratification in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) has a low risk for sudden cardiac death (SCD). The ESC clinical risk prediction model estimates the risk of SCD using clinical and echocardiographical parameters without taking into account cardiac magnetic resonance (CMR) parameters. Therefore, we compared the CMR characteristics of 149 patients with low, intermediate and high ESC risk scores. In these patients left and right ventricular ejection fraction and volumes were comparable. Patients with a high ESC risk score revealed a significantly higher extent of late gadolinium enhancement (LGE) compared to patients with intermediate or a low risk scores. During follow-up of 4 years an extent of LGE ≥20% identified patients at a higher risk for major adverse cardiac arrhythmic events in the low and intermediate ESC risk group whereas an extent of LGE <20% was associated with a low risk of major adverse cardiac arrhythmic events despite a high ESC risk score ≥6%. Hence, we hypothesize that the extent of fibrosis might be an additional risk marker.

[A life-saving shock from a subcutaneous ICD during skydiving]. / Lebensrettender Schock durch einen subkutanen ICD während eines Fallschirmsprungs.

We report the case of a 38-year-old man who was implanted a subcutaneous implantable cardioverter-defibrillator (S-ICD) and then performed a skydive from a height of 3000 m. During the jump, he lost consciousness due to ventricular fibrillation (VF). The S­ICD detected the VF properly and successfully shocked the arrhythmia. Our illustrative case emphasizes the S­ICD as an appropriate therapy in patient with life-threatening arrhythmias even under extreme conditions.

Novel Prognostic Markers Derived from Cardiovascular Magnetic Resonance Imaging in Patients with Stable Chronic Coronary Artery Disease.

BACKGROUND: In patients with coronary artery disease (CAD), risk stratification remains a challenge. Recently, epicardial adipose tissue (EAT) assessed by cardiovascular magnetic resonance imaging (CMRI) has emerged as a new marker in patients with CAD. Thus, we aimed to investigate the association of CMR parameters with all-cause and cardiac mortality in patients with CAD. PATIENTS AND METHODS: CMRI examination was performed in 260 patients with CAD. RESULTS: In the 40 patients who died, left ventricular (LV) ejection fraction, right ventricular fractioning shortening, LV remodeling index and indexed EAT were significantly reduced, whereas LV mass index, LV end-diastolic volume index, LV end-systolic volume index, LV end-diastolic diameter and the extent of late gadolinium enhancement expressed as a percentage of the maximum possible score to estimate the extent of LGE relative to LV mass (LGE %), were significantly elevated. Using multivariate analysis, age, LV mass index, extent of LGE % and indexed EAT proved to be independently associated with all-cause and cardiac mortality. CONCLUSION: Age, LV mass index, the extent of LGE % and indexed EAT are independent predictors of mortality that might contribute to a more accurate risk stratification of patients with CAD.

Impact of shocks on mortality in patients with ischemic or dilated cardiomyopathy and defibrillators implanted for primary prevention.

BACKGROUND: Emerging interest is seen in the paradox of defibrillator shocks for ventricular tachyarrhythmia and increased mortality risk. Particularly in patients with dilated cardiomyopathy (DCM), the prognostic importance of shocks is unclear. The purpose of this study was to compare the outcome after shocks in patients with ischemic cardiomyopathy (ICM) or DCM and defibrillators (ICD) implanted for primary prevention. METHODS AND RESULTS: Data of 561 patients were analyzed (mean age 68.6±10.6 years, mean left ventricular ejection fraction 28.6±7.3%). During a median follow-up of 49.3 months, occurrence of device therapies and all-cause mortality were recorded. 74 out of 561 patients (13.2%) experienced ≥1 appropriate and 51 out of 561 patients (9.1%) ≥1 inappropriate shock. All-cause mortality was 24.2% (136 out of 561 subjects). Appropriate shock was associated with a trend to higher mortality in the overall patient population (HR 1.48, 95% CI 0.96-2.28, log rank p = 0.072). The effect was significant in ICM patients (HR 1.61, 95% CI 1.00-2.59, log rank p = 0.049) but not in DCM patients (HR 1.03, 95% CI 0.36-2.96, log rank p = 0.96). Appropriate shocks occurring before the median follow-up revealed a much stronger impact on mortality (HR for the overall patient population 2.12, 95% CI 1.24-3.63, p = 0.005). The effect was driven by ICM patients (HR 2.48, 95% CI 1.41-4.37, p = 0.001), as appropriate shocks again did not influence survival of DCM patients (HR 0.63, 95% CI 0.083-4.75, p = 0.65). Appropriate shocks occurring after the median follow-up and inappropriate shocks occurring at any time revealed no impact on survival in any of the groups (p = ns). CONCLUSION: Appropriate shocks are associated with reduced survival in patients with ICM but not in patients with DCM and ICDs implanted for primary prevention. Furthermore, the negative effect of appropriate shocks on survival in ICM patients is only evident within the first 4 years after device implantation.

Comparison of ventricular tachyarrhythmia characteristics in patients with idiopathic dilated or ischemic cardiomyopathy and defibrillators implanted for primary prevention.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy for primary prevention is well established in ischemic cardiomyopathy (ICM). Data on the role of ICDs in patients with dilated cardiomyopathy (DCM) and no history of ventricular tachyarrhythmia (VT/VF) are more limited. HYPOTHESIS: DCM patients with an impaired left ventricular ejection fraction (LVEF) still represent a low arrhythmic risk subgroup in clinical practice. METHODS: ICD stored data of DCM patients with an LVEF ≤35% was compared to data of ICM patients meeting Multicenter Automatic Defibrillator Implantation Trial (MADIT) eligibility criteria. VT/VF occurrences and electrical storm (ES) events were analyzed. RESULTS: There were 652 patients followed for 50.9 ± 33.9 months. There were 1978 VT and 241 VF episodes analyzed in 66 out of 203 patients (32.5%) with DCM and in 118 out of 449 patients (26.3%, P = 0.209) with ICM. Freedom of appropriate ICD treatment due to VT/VF or ES events did not differ in both patient populations (log-rank, P>0.05). In patients presenting with VT/VF episodes, mean event rates were comparable in both patient populations (3.2 ± 14.1 for DCM and VT vs 3 ± 13.9 for ICM and VT [P = 0.855], 0.4 ± 1.3 for DCM and VF vs 0.4 ± 1.8 for ICM and VF [P = 0.763], and 0.2 ± 0.7 for DCM and ES vs 0.2 ± 1 for ICM and ES [P = 0.666]). CONCLUSIONS: DCM patients with prophylactic ICDs implanted due to heart failure and patients fulfilling MADIT criteria reveal comparable patterns of VT/VF/ES events during long-term follow-up. Incidence, mean number of events, and time to first event did not differ significantly. Findings support the current guidelines for prophylactic ICD therapy in DCM patients with heart failure.

Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure.

AIMS: In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular (LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy. METHODS AND RESULTS: This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients [age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%]. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year. CONCLUSIONS: This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.

Predictors of electrical storm recurrences in patients with implantable cardioverter-defibrillators.

AIMS: To determine prevalence and predictors of electrical storm recurrences (ES-Rs) in patients with implantable cardioverter-defibrillators (ICDs) as electrical storms (ESs) represent serious clinical events carrying a high risk of mortality. METHODS AND RESULTS: Single-centre study analysing data of consecutive patients receiving an ICD between 1993 and 2008. Electrical storm was defined as ≥ 3 separate ventricular tachyarrhythmic (VT/VF) episodes ≤ 24 h. Nine hundred and fifty-five patients [mean left ventricular ejection fraction (LVEF) 35.7 ± 15.6%] were prospectively followed for 54.2 ± 35.5 months. In 274 of 955 patients (28.7%), 2871 VT/VF episodes were observed. One hundred and fifty-three ES episodes occurred in 63 of 955 patients (6.6%). Thirty-two of 63 patients (50.8%) experienced ≥ 2 ES episodes. Twenty-six of 32 patients (81.2%) with ES-Rs experienced the second ES episode within 1 year after the initial event. Cox regression analysis identified an LVEF ≤ 30% (OR 2.2; 95% CI 1.021-4.856; P = 0.044) and a patient's age >65 years (OR 3.5; 95% CI 1.207-10.176; P = 0.021) to be predictive for ES-Rs. Patients with angiotensin-converting enzyme (ACE) inhibitor therapy were less likely to experience ES-Rs (OR 0.39; 95% CI 0.187-0.817; P = 0.013). CONCLUSIONS: Electrical storm events are not rare in a 'real-world' patient population with ICDs (6.6% in 4.5 years). The risk for ES-Rs, especially within the first year after the initial event, is high. Left ventricular ejection fraction ≤ 30%, age >65 years, and a lack of ACE inhibitor therapy are independent predictors of ES-R.

Prevention of inappropriate ICD shocks in patients with Brugada syndrome.

BACKGROUND: In Brugada syndrome implantable cardioverter defibrillator (ICD) therapy is associated with a high rate of inappropriate therapies, mainly due to supraventricular tachyarrhythmias (SVT) (2.7-14.1%/year). Aim of the present study was to evaluate a single ventricular fibrillation (VF) detection zone with a high cut-off rate with respect to prevention of inappropriate ICD shock due to SVT and safety of this programming. METHODS: Sixty-one consecutive patients (mean age 42.6 +/- 12.9 years; 41 males) diagnosed with Brugada syndrome and implanted with an ICD were included. ICDs were prospectively programmed with a single VF detection zone and a cut-off rate of 222 beats/minute (bpm). A maximum of six shocks with the maximal shock energy were programmed. The minimal follow-up was 1 year. RESULTS: During a follow-up of 47.6 +/- 23.1 months seven patients (2.91%/year) received appropriate ICD shocks. No patient suffered from syncope or died. Five patients (2.07%/year) received inappropriate ICD shocks: four patients due to T-wave oversensing and only one patient (0.4%/year) due to SVT (atrial fibrillation with a ventricular rate of >222 bpm). CONCLUSIONS: Programming of a single, high-rate VF zone in patients with Brugada syndrome and an implanted defibrillator is safe. Such programming may be associated with reduced inappropriate defibrillator discharges. A single detection zone with a high VF cut-off rate can be recommended in patients with Brugada syndrome.

Role of proinflammatory markers and NT-proBNP in patients with an implantable cardioverter-defibrillator and an electrical storm.

BACKGROUND: Several studies have attempted to identify risk factors for the development of an electrical storm (ES), which is defined as 3 separate ventricular tachyarrhythmic (VT/VF) events, but in the majority of studies no triggers have been found. However, little is known about the role of inflammation and NT-proBNP in patients with ES. The aim of this study was therefore to assess the relationship of Interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and NT-proBNP serum concentrations in ICD-patients with or without single spontaneous ventricular tachyarrhythmic events (VT/VF) and in ES. METHODS: Markers were determined in 51 patients without ICD-intervention, in 15 ICD-patients with single VT/VF-episodes during 9-months follow-up and in 20 ICD-patients with ES (blood sampling performed within 60min after fulfilling ES criteria). VT/VF-episodes were analysed by stored ICD-electrograms. RESULTS: All patients had idiopathic dilated cardiomyopathy (n=23) or coronary artery disease (n=63). Patients with ES revealed significantly higher mean serum concentrations of all markers (IL-6 15.19+/-10.34 pg/mL, hs-CRP 20.12+/-14.4 mg/L, NT-proBNP 4799+/-4596 pg/mL) compared to baseline values of patients with single VT/VF-events during follow-up (IL-6 8.37+/-5.8 pg/mL (p=0.03), hs-CRP 4.7+/-5.3 mg/dL (p<0.001), NT-proBNP 1913+/-2665pg/mL (p=0.04)) and compared to baseline values of ICD-patients without device intervention (IL-6 4.62+/-3.66 pg/mL (p<0.001), hs-CRP 4.1+/-3.4 mg/L (p<0.001), NT-proBNP 1461+/-2281pg/mL (p<0.001)). In 9/20 patients presenting with ES (45%) baseline values were available. All markers were significantly higher during ES compared to event-free determination (IL-6 14.54+/-10.43 vs. 7.03+/-2.83 pg/mL (p=0.04), hs-CRP 19.07+/-16.07 vs. 6.5+/-3.9 mg/L (p=0.02), NT-proBNP 4218+/-2561 vs. 2099+/-1279 pg/mL (p=0.03)). CONCLUSIONS: Electrical storm is associated with significantly elevated IL-6, hs-CRP and NT-proBNP serum concentrations in ICD-patients with structural heart disease. Thus, ES may be triggered by proinflammatory activity. Combined intraindividual elevation of determined markers might help to identify patients at risk of impending electrical storm.

Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.

AIMS: The diagnostic type I ECG in Brugada syndrome (BS) is often concealed and fluctuates between the diagnostic and non-diagnostic pattern. Challenge with intravenous ajmaline is used to unmask the diagnostic Brugada ECG. The aim of this study was to evaluate the safety of the test and to identify predictors for the response to an intravenous ajmaline challenge. METHODS AND RESULTS: In four tertiary referral centres, 677 consecutive patients underwent an intravenous ajmaline challenge for diagnosis or exclusion of BS in accordance with the recommendations of the Brugada consensus conferences. Two hundred and sixty-two ajmaline challenges (39%) were positive. Male gender, familial BS, sudden cardiac arrest (SCA), first-degree AV-block, basal saddleback type ECG, and basal right bundle branch block were identified as predictors for a positive ajmaline challenge. A predictor for negative ajmaline test was the absence of ST-segment elevation at baseline. Six of 12 patients who had experienced SCA, and five of 25 patients with a familial sudden death exhibited a positive response to ajmaline. Only one patient (0.15%) developed sustained ventricular tachyarrhythmias (ventricular fibrillation) during ajmaline challenge, which was terminated by a single external defibrillator shock. CONCLUSION: Ajmaline challenge is a safe procedure to unmask the electrocardiographic pattern of BS. Electrocardiographic and clinical parameters were identified to predict patients' response to ajmaline. The results of this study guide the clinician in which setting an ajmaline challenge is an appropriate diagnostic step.

Prospective study of interleukin-6 and the risk of malignant ventricular tachyarrhythmia in ICD-recipients--a pilot study.

OBJECTIVE: We investigated the relationship between interleukin-6 (IL-6) and the risk of experiencing spontaneous ventricular tachyarrhythmia (VT/VF) in patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: Cytokine levels predict outcome in patients with advanced heart failure and are elevated in patients with coronary artery disease (CAD). Regarding heart rhythm disturbances, proinflammatory activity could predict the occurrence of atrial fibrillation. There is no data on cytokine levels and the risk of spontaneous VT/VF. METHODS: IL-6 serum concentrations were determined at baseline and follow-up in 47 consecutive ICD-patients with CAD and idiopathic dilated cardiomyopathy (IDC). Data were prospectively correlated with VT/VF-incidence. RESULTS: Thirty-six patients (76.6%) suffered from CAD and 11 (23.4%) from IDC. Mean serum concentrations of IL-6 at baseline and at 9 months follow-up were 6.12+/-4.98 and 4.63+/-6.97. 88 spontaneous VT/VF-events occurred in 13/47 patients (27.7%). Patients with VT/VF had significantly higher IL-6 levels as compared to patients without VT/VF (8.96+/-5.97 vs. 5.04+/-4.16pg/ml at baseline (p =0.03), 7.8+/-4.88 vs. 3.42+/-6.32pg/ml at follow-up (p =0.01)). CONCLUSIONS: Elevated IL-6 serum concentrations were prospectively associated with an increased risk of spontaneous VT/VF-events in ICD-patients with CAD or IDC. These preliminary findings support a possible association of proinflammatory activity and an increased susceptibility to spontaneous VT/VF-events.